Beta-secretase 1 (also known as beta-site amyloid precursor protein cleaving enzyme 1, BACE1, memapsin-2 and aspartyl protease 2) cleaves amyloid precursor protein (APP) to form an extracellular fragment (sAPPβ) and a 99 amino acid residue cell membrane bound fragment (CTFβ). The CTFβ fragment is further processed by gamma-secretase to form amyloid-β peptides of either 40 amino acids (Aβ-40) or 42 amino acids (Aβ-42). These amyloid-β peptides are involved in Alzhiemer's disease pathology, with Aβ-42 considered the more detrimental species. In mutations of APP that are associated with Alzheimer's disease, the production of Aβ-42 is increased relative to Aβ-40. Aβ peptides are also relevant to the processing of tau. Alzheimer's disease, a common form of dementia, is a progressive degenerative disease that is characterized by two major pathologic observations in the brain which are (1) neurofibrillary tangles, which are aggregates of hyperphosphorylated tau proteins, and (2) amyloid-β plaques, which form from insoluble aggregates of amyloid-β peptides. See, for example, O'Brien and Wong, Annual Review of Neuroscience 2011, 34:185-204. The disease results in memory loss and impaired cognitive ability, and current therapy is limited to treating the symptoms. The inhibition of BACE1 is considered a desirable pharmaceutical target, as inhibition of BACE1 is likely to slow the progression of diseases resulting in β-amyloidosis, such as Alzheimer's disease.
An extra copy of chromosome 21 is found in individuals with Down syndrome. This chromosome contains the gene encoding APP, as well as the gene encoding BACE2 (a closely related homolog to BACE1). Down syndrome patients tend to develop Alzheimer's disease at an early age. The additional APP gene is believed to result in overexpression of APP resulting in an increase in Aβ peptides, which could explain the early onset of Alzheimer's disease in these individuals. As such, inhibition of BACE1 is considered a desirable pharmaceutical target in treating Down syndrome (Jiang et al., PNAS Jan. 26, 2010, 107(4):1630-1635).
Beta-secretase 2 (BACE2) is expressed in the pancreas, and is believed to be involved in the processing of pancreatic β-cells and may have a role in diabetes-associated amyloidogenesis. See, for example, Esterhazy et al, Cell Metab. 2011, Sep. 7, 14(3):365-77; and Finzi et al., Ultrastructural Pathology 2008, November-December, 32(6):246-51. The inhibition of BACE2 is considered a desirable pharmaceutical target, for example in the treatment of type 2 diabetes.
A number of other diseases involve β-amyloidosis, or are otherwise desirable targets for treatment with an inhibitor of BACE1 and/or BACE2. These include amyotrophic lateral sclerosis (Rabinovich-Toidman et al., Neurodegenerative Disease 2012, Jan. 21; Koistinen et al., Muscle Nerve 2006, October, 34(4):444-50), cerebral amyloid angiopathy (Blaise et al., The Aging Cell 2012, Jan. 19; Zipfel et al., Stroke 2009, March, 40(3 Suppl):S16-S19), retinal diseases, such as glaucoma and age-related macular degeneration (Guo et al., PNAS 2007, Aug. 14, 104(33):13444-13449; Bruban et al., Adv Exp Med Biol. 2012, 723:67-74; Ding et al., PNAS 2011, Jul. 12, 108(28):E279-E287), cardiovascular related disorders, such as cardiac arrest, stroke, or ischemia (Zetterberg et al., PLoS ONE 2011, 6(12):e28263; Xiong et al., Neurobiology of Disease 2008, 32:433-441; Wen et al., Brain Research 2004, May 29, 1009(1-2):1-8), disorders involving demyelination, such as nerve injury, spinal cord injury, and multiple sclerosis (Farah et al., The Journal of Neuroscience, 2011, Apr. 13, 31(15):5744-5754), and inclusion body myositis (Jin et al., American Journal of Pathology December 1998, 153(6):1679-1686; Nogalska et al., Neurosci. Lett. 2010, May 3, 474(3):140-143).
Alzheimer's disease affects a large population of elderly people, and there are few options available at this time to combat this disease. As such, a considerable effort has been made to find a suitable BACE1 inhibitor. For example, BACE1 and/or BACE2 inhibitors are described in a large number of patent applications, including PCT publication numbers WO 2012057247, WO 2012057248, WO 2012147762, WO 2012147763, WO 2011071135, WO 2011071057, WO 2011070781, WO 2011069934, WO 2011058763, WO 2011005738, and WO 2009134617, US patent application publication numbers US 2010190279, US 2010160290, US 2010093999, US 20100075957, US 2009209755, US 2009082560, and US 20070287692, and US patent numbers U.S. Pat. No. 7,964,594, U.S. Pat. No. 7,759,353, and U.S. Pat. No. 7,592,348. One such BACE1 inhibitor has been tested in human clinical trials (May et al., Journal of Neuroscience, 2011, Nov. 16, 31(46):16507-16516).
In spite of considerable effort from several companies to find a suitable BACE1 inhibitor, few have made it into the clinic. There remains a need to find a suitable BACE1 inhibitor that is pharmaceutically active in the brain without unwanted side effects.